JP7167027B2 - 抗pcsk9抗体およびその使用 - Google Patents
抗pcsk9抗体およびその使用 Download PDFInfo
- Publication number
- JP7167027B2 JP7167027B2 JP2019534112A JP2019534112A JP7167027B2 JP 7167027 B2 JP7167027 B2 JP 7167027B2 JP 2019534112 A JP2019534112 A JP 2019534112A JP 2019534112 A JP2019534112 A JP 2019534112A JP 7167027 B2 JP7167027 B2 JP 7167027B2
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- Prior art keywords
- amino acid
- acid sequence
- seq
- antibody
- pcsk9
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96402—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from non-mammals
- G01N2333/96405—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from non-mammals in general
- G01N2333/96408—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from non-mammals in general with EC number
- G01N2333/96411—Serine endopeptidases (3.4.21)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Cell Biology (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Mycology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022164233A JP2023002635A (ja) | 2016-12-24 | 2022-10-12 | 抗pcsk9抗体およびその使用 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611210645.3A CN108239150A (zh) | 2016-12-24 | 2016-12-24 | 抗pcsk9抗体及其用途 |
| CN201611210645.3 | 2016-12-24 | ||
| PCT/CN2017/118050 WO2018113781A1 (zh) | 2016-12-24 | 2017-12-22 | 抗pcsk9抗体及其用途 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022164233A Division JP2023002635A (ja) | 2016-12-24 | 2022-10-12 | 抗pcsk9抗体およびその使用 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2020506670A JP2020506670A (ja) | 2020-03-05 |
| JP2020506670A5 JP2020506670A5 (enExample) | 2020-11-12 |
| JP7167027B2 true JP7167027B2 (ja) | 2022-11-08 |
Family
ID=62624551
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019534112A Active JP7167027B2 (ja) | 2016-12-24 | 2017-12-22 | 抗pcsk9抗体およびその使用 |
| JP2022164233A Pending JP2023002635A (ja) | 2016-12-24 | 2022-10-12 | 抗pcsk9抗体およびその使用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022164233A Pending JP2023002635A (ja) | 2016-12-24 | 2022-10-12 | 抗pcsk9抗体およびその使用 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US11485795B2 (enExample) |
| EP (1) | EP3560961A4 (enExample) |
| JP (2) | JP7167027B2 (enExample) |
| KR (1) | KR102331021B1 (enExample) |
| CN (2) | CN108239150A (enExample) |
| AU (1) | AU2017379048B2 (enExample) |
| BR (1) | BR112019012648A2 (enExample) |
| CA (1) | CA3047049C (enExample) |
| WO (1) | WO2018113781A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023002635A (ja) * | 2016-12-24 | 2023-01-10 | イノベント バイオロジックス (スウツォウ) カンパニー,リミテッド | 抗pcsk9抗体およびその使用 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110464842B (zh) * | 2018-05-11 | 2022-10-14 | 信达生物制药(苏州)有限公司 | 包含抗pcsk9抗体的制剂及其用途 |
| TWI759867B (zh) * | 2019-09-19 | 2022-04-01 | 大陸商信達生物製藥(蘇州)有限公司 | 抗前蛋白轉化酶枯草桿菌蛋白酶/kexin型9抗體用於製備治療膽固醇相關疾病之藥物的用途 |
| CA3160071A1 (en) * | 2019-11-18 | 2021-05-27 | Ad Pharmaceuticals Co., Ltd. | Anti-pcsk9 antibody and use thereof |
| CN116983434B (zh) * | 2023-09-28 | 2024-03-15 | 康霖生物科技(杭州)有限公司 | 用于基因治疗的核酸构建体及其用途 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010536384A (ja) | 2007-08-23 | 2010-12-02 | アムジエン・インコーポレーテツド | プロタンパク質コンベルターゼスブチリシンケクシン9型(pcsk9)に対する抗原結合タンパク質 |
| JP2012504388A (ja) | 2008-09-12 | 2012-02-23 | ライナット ニューロサイエンス コーポレイション | Pcsk9拮抗薬 |
| JP2012511913A (ja) | 2008-12-15 | 2012-05-31 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Pcsk9に対する高親和性ヒト抗体 |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4737456A (en) | 1985-05-09 | 1988-04-12 | Syntex (U.S.A.) Inc. | Reducing interference in ligand-receptor binding assays |
| DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
| GB9114948D0 (en) | 1991-07-11 | 1991-08-28 | Pfizer Ltd | Process for preparing sertraline intermediates |
| WO1993006217A1 (en) | 1991-09-19 | 1993-04-01 | Genentech, Inc. | EXPRESSION IN E. COLI OF ANTIBODY FRAGMENTS HAVING AT LEAST A CYSTEINE PRESENT AS A FREE THIOL, USE FOR THE PRODUCTION OF BIFUNCTIONAL F(ab')2 ANTIBODIES |
| US5789199A (en) | 1994-11-03 | 1998-08-04 | Genentech, Inc. | Process for bacterial production of polypeptides |
| US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
| US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
| US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
| EP1740946B1 (en) | 2004-04-20 | 2013-11-06 | Genmab A/S | Human monoclonal antibodies against cd20 |
| JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
| JP5537813B2 (ja) * | 2006-02-14 | 2014-07-02 | エクソンモービル・ケミカル・パテンツ・インク | Mcm−22型モレキュラーシーブの製造方法 |
| US7572618B2 (en) | 2006-06-30 | 2009-08-11 | Bristol-Myers Squibb Company | Polynucleotides encoding novel PCSK9 variants |
| US8877688B2 (en) | 2007-09-14 | 2014-11-04 | Adimab, Llc | Rationally designed, synthetic antibody libraries and uses therefor |
| CA2697193C (en) | 2007-09-14 | 2017-06-06 | Adimab, Inc. | Rationally designed, synthetic antibody libraries and uses therefor |
| AR070316A1 (es) | 2008-02-07 | 2010-03-31 | Merck & Co Inc | Antagonistas de pcsk9 (proproteina subtilisina-kexina tipo 9) |
| WO2012009568A2 (en) | 2010-07-16 | 2012-01-19 | Adimab, Llc | Antibody libraries |
| MX344727B (es) | 2010-11-11 | 2017-01-05 | Abbvie Biotechnology Ltd | Formulaciones liquidas de anticuerpos anti-tnf-alfa de alta concentracion mejoradas. |
| JOP20200043A1 (ar) | 2011-05-10 | 2017-06-16 | Amgen Inc | طرق معالجة أو منع الاضطرابات المختصة بالكوليسترول |
| AR087305A1 (es) | 2011-07-28 | 2014-03-12 | Regeneron Pharma | Formulaciones estabilizadas que contienen anticuerpos anti-pcsk9, metodo de preparacion y kit |
| EA039663B1 (ru) | 2012-05-03 | 2022-02-24 | Амген Инк. | Применение антитела против pcsk9 для снижения сывороточного холестерина лпнп и лечения связанных с холестерином расстройств |
| CN105001336A (zh) * | 2014-04-18 | 2015-10-28 | 上海复旦张江生物医药股份有限公司 | Pcsk9拮抗剂 |
| WO2015200438A1 (en) | 2014-06-24 | 2015-12-30 | Eleven Biotherapeutics, Inc. | High affinity antibodies against pcsk9 |
| CN106084058B (zh) * | 2015-07-15 | 2019-08-27 | 北京天广实生物技术股份有限公司 | 抗人pcsk9单克隆抗体 |
| CN105348390B (zh) * | 2015-10-26 | 2018-08-28 | 北京智仁美博生物科技有限公司 | 抗人pcsk9单克隆抗体 |
| CN105801701B (zh) * | 2016-03-31 | 2019-03-29 | 河北仁博科技有限公司 | 一种pcsk9抗体的重链和轻链可变区及其应用 |
| CN108239150A (zh) * | 2016-12-24 | 2018-07-03 | 信达生物制药(苏州)有限公司 | 抗pcsk9抗体及其用途 |
| JP7377596B2 (ja) | 2017-02-22 | 2023-11-10 | アムジエン・インコーポレーテツド | 低粘度、高濃度エボロクマブ製剤及びそれらの製造方法 |
| CN110464842B (zh) | 2018-05-11 | 2022-10-14 | 信达生物制药(苏州)有限公司 | 包含抗pcsk9抗体的制剂及其用途 |
-
2016
- 2016-12-24 CN CN201611210645.3A patent/CN108239150A/zh active Pending
-
2017
- 2017-12-22 BR BR112019012648-1A patent/BR112019012648A2/pt active Search and Examination
- 2017-12-22 AU AU2017379048A patent/AU2017379048B2/en active Active
- 2017-12-22 CA CA3047049A patent/CA3047049C/en active Active
- 2017-12-22 JP JP2019534112A patent/JP7167027B2/ja active Active
- 2017-12-22 KR KR1020197021287A patent/KR102331021B1/ko active Active
- 2017-12-22 US US16/473,245 patent/US11485795B2/en active Active
- 2017-12-22 EP EP17883464.4A patent/EP3560961A4/en active Pending
- 2017-12-22 WO PCT/CN2017/118050 patent/WO2018113781A1/zh not_active Ceased
- 2017-12-22 CN CN201780080278.6A patent/CN110177810B/zh active Active
-
2022
- 2022-10-12 JP JP2022164233A patent/JP2023002635A/ja active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010536384A (ja) | 2007-08-23 | 2010-12-02 | アムジエン・インコーポレーテツド | プロタンパク質コンベルターゼスブチリシンケクシン9型(pcsk9)に対する抗原結合タンパク質 |
| JP2012504388A (ja) | 2008-09-12 | 2012-02-23 | ライナット ニューロサイエンス コーポレイション | Pcsk9拮抗薬 |
| JP2012511913A (ja) | 2008-12-15 | 2012-05-31 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Pcsk9に対する高親和性ヒト抗体 |
Non-Patent Citations (1)
| Title |
|---|
| ALKINDI, M. et al.,Monoclonal Antibodies for the Treatment of Hypercholesterolemia: Targeting PCSK9,Canadian Journal of Cardiology,Vol. 32, No. 12,P. 552-1560,https://doi.org/10.1016/j.cjca.2016.04.013 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023002635A (ja) * | 2016-12-24 | 2023-01-10 | イノベント バイオロジックス (スウツォウ) カンパニー,リミテッド | 抗pcsk9抗体およびその使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20190096411A (ko) | 2019-08-19 |
| CN110177810A (zh) | 2019-08-27 |
| CA3047049A1 (en) | 2018-06-28 |
| JP2020506670A (ja) | 2020-03-05 |
| KR102331021B1 (ko) | 2021-11-26 |
| EP3560961A4 (en) | 2020-12-23 |
| CA3047049C (en) | 2023-10-24 |
| CN110177810B (zh) | 2022-10-18 |
| AU2017379048A1 (en) | 2019-07-25 |
| CN108239150A (zh) | 2018-07-03 |
| JP2023002635A (ja) | 2023-01-10 |
| BR112019012648A2 (pt) | 2020-01-28 |
| EP3560961A1 (en) | 2019-10-30 |
| AU2017379048B2 (en) | 2020-08-27 |
| US11485795B2 (en) | 2022-11-01 |
| WO2018113781A1 (zh) | 2018-06-28 |
| US20200087416A1 (en) | 2020-03-19 |
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